At present, no effective therapy is available for metastatic pancreatic cancer. This proposal seeks to overcome this impasse by employing a novel approach employing a cancer-specific conditionally replication competent adenovirus that expresses a therapeutic cytokine, IFN-? or mda-7/IL-24 (a cancer terminator virus (CTV)), in combination with an ultrasound (US) contrast agent and US waves. These studies are based on the observations that IFN-? and mda-7/IL-24 displays selective anti-pancreatic cancer activity, potent 'bystander'anti-tumor activity, anti-angiogenic activity. Based on profound multifunctional, selective anti-cancer activities of mda-7/IL-24, this gene has been evaluated in a Phase I clinical trial in patients with advanced cancers, not including pancreatic cancer, by repeat intratumoral injections with a non-replicating adenovirus (Ad) expressing mda-7/IL-24 (Ad.mda-7;INGN 241). This therapeutic approach was safe and resulted in significant clinical activity. Restrictions of Ad-based therapies include rapid degradation and clearance by the immune system, thus limiting systemic applications. By using US contrast agents (microbubbles) we will achieve both specificity of action as well as protection of the viral vectors from inactivation. Additionally, the gas filled microspheres effectively lower the energy threshold for cavitation allowing diagnostic transducers operating within the energy levels mandated by the FDA to be used for drug/gene delivery. In the sonification zone the microbubbles undergo cavitation, destroying the bubbles and releasing their contents, creating small shockwaves that increase cell permeability. This has been shown to increase transcapillary passage of macromolecules or nanospheres co-delivered by the microbubbles in experimental animals. In principle, the present approach should allow efficient CTV delivery and may evoke a cure in both primary and distant mestastatic pancreatic cancer, which will be tested in immune incompetent animal models. Successful accomplishment of these studies will pave the way for future clinical trials. PUBLIC HEALTH RELEVANCE: The present study seeks to develop an effective therapy for pancreatic cancer that employs cancer-specific apoptosis-inducing cytokines, IFN-? or mda-7/IL-24, delivered by a conditionally replication competent adenovirus, a cancer terminator virus (CTV), in combination with ultrasound contrast agents and ultrasound waves. This novel approach will permit efficient systemic delivery of the CTV to tumors, offering the potential to develop a 'cure'for both localized and metastatic pancreatic cancer. Successful achievement of the objectives of the present proposal will provide for rapid translation into the clinic as a new and potentially effective therapy for metastatic pancreatic cancer.